This invention relates to a method for improving primary memory and/or learning, employing a 5-hydroxytryptamine receptor agonist which is selective for the 5-hydroxytryptamine-1-A receptor subtype.
Heretofore, various agents have been reported to improve memory. For example, these have included nicotine, caffeine, amphetamine, strychnine and picrotoxin. Additionally, fluoxetine (U.S. Pat. No. 4,647,591) and certain alpha-2I selective adrenergic receptor agonists (U.S. Pat. No. 4,847,300) have been reported as memory improving agents.
Studies have evidenced that the hippocampus plays an important role in learning and memory. Certain electrical activity exhibited by the hippocampus (electroencephalographic (EEG)), in particular the hippocampal theta rhythm (4 to 9 hertz), has been reported to be an important temporal correlate of memory storage and sensory processing. See, e.g. Landfield, P. W., J. L. McGaugh and R. J. Tusa, "Theta Rhythm: A temporal Correlate of Memory Storage Processes in the Rat", Science 175: 87-89, (1972); and Klemm, W. R., "Hippocampal EEG and Information Processing: A special Role for Theta Rhythm", Prog. in Neurobiol. 7, 197-21 (1976). Studies have also evidenced that the hippocampal theta rhythm is predictive of the rate of learning. Berry, S. D. and R. F. Thompson, "Prediction of Learning Rate from the Hippocampal ElectroencePhalogram", Science, 200, 1289-1300 (1978). For additional information as to the role of the hippocampus and memory, reference can be made to Paxinos, George, The Human Nervous System, pp. 745-746 (1990).
It is also well-known that this hippocampal theta rhythm is dependent on cholinergic activity, and treatments that inhibit cholinergic activity inhibit both the theta rhythm and short term memory. Bland, B. H., M. G. Seto, B. R. Sinclair and S. M. Fraser, "The Pharmacology of Hippocampal Theta Cells: Evidence that the Sensory Processing Correlate is Cholinergic ", Brain Research, 229, 121-131 (1984).
Studies have also indicated that 5-hydroxytryptamine (also known as serotonin) has a role in memory and learning, and that certain serotonin reuptake inhibitors can improve memory. See, e.g., Altman, H. J. et al., "Role of serotonin in memory: Facilitation by alaproclate and zimeldine", Psycopharm., 84, 496-502 (1984); and U.S. Pat. No. 4,647,591 (fluoxetine).
5-Hydroxytryptamine (hereinafter sometimes referred to as "5-HT") receptors in the central nervous system (CNS) have been the subject of substantial attention over the past decade. Multiple 5-HT receptor subtypes in the CNS have been identified. Originally, these 5-HT recognition sites were classified into two subtypes. A subset of 5-HT receptors which bound [.sup.3 H]-5-HT with high affinity was designated 5-HT.sub.1, and a subset which bound [.sup.3 H]-spiperone with high affinity was designated 5-HT.sub.2. See, Peroutka, S. J. and Snyder, S. H., Mol. Pharmacol., 16. 687 (1979). Since then, 5-HT.sub.1 receptors have been subdivided into four classes, 5-HT.sub.1A, 5-HT.sub.1B, 5-HT.sub.1C, and 5-HT.sub.1D. See, e.g., Pedigo, N. W. et al., J. Neurochem., 36, 220 (1981); Hoyer, D. et al., Eur. J. Pharmacol., 118, 13, 1985; Peroutka, S. J., J. Neurochem., 47, 529 (1986); and Heuring, R. E. et al., J. Neurosci., 7, 894 (1987). Additionally, another subtype of 5-HT receptor, the 5-HT.sub.3 receptor, has been identified. Further, it has been recognized that 5-HT agonists which act at different 5-HT receptors can product opposite effects in a given system. For example, it is known that both 5-HT.sub.1A and 5-HT.sub.2 agonists effect thermoregulation. However, 5-HT.sub.1A agonists produce a hypothermic response, while 5-HT.sub.2 agonists produce a hyperthermic response. See, Glennon, J. Med. Chem., 30, pp. 1-12 (1987). Furthermore, the differential effects of 5-HT agonists which are selective for specific subtypes is not limited to thermoregulation, but also include other physiological phenomena.
The present invention relates to the use of 5-HT receptor agonists which are selective for the 5-HT-1A subtype (i.e. selective 5-HT.sub.1A agonists) to improve primary memory and/or learning functions. Several such selective 5-HT.sub.1A agonists have been identified and reported in the literature. These selective agonists may be for instance, indoles (see. e.g. U.S. Pat. No. 4,576,959), arylpiperazines, aminotetralins, benzodioxanes, pyrimidinylpiperazines, or aryloxypropanolamines. Perhaps best known thus far is the aminotetralin, 8-hydroxy-2(di-n-propylamino)tetralin (8-OH-DPAT), which has been identified as the prototypic selective 5-HT.sub.1A agonist. See, e.g., Glennon, R. A., J. Med. Chem., 30, 1, pp. 1-12 (1987). Several reviews on the subject exist, to which reference may be made for further information as to selective 5-HT.sub.1A and other 5-HT agonists. See, e.g., Robertson, D. W. et al., Annu. Rep. Med. Chem., 23, pp. 49-58 (1988); Johnson, G., Annu. Rep. Med. Chem., 22, 41 (1987); Fozard, J. R., Trends Pharmacol. Sci, 8, 501 (1987); and Green, J., Trends Pharmacol. Sci, 8, 90 (1987).
As to physiological effects, to date, selective 5-HT.sub.1A agonists have been reported to produce hyperphagia and hypothermia, to stimulate sexual behavior, to be anxiolytic, and to cause the 5-HT behavioral syndrome.
No reports have been made that selective 5-HT.sub.1A agonists induce hippocampal theta rhythm and thus may be used as excellently suited agents for affecting and improving primary memory and/or learning functions associated with hippocampal theta rhythm. The present invention is based on the discovery of this phenomenon.